Over 10 million people in the USA have diabetes mellitus (DM), and it is a leading cause of morbidity and mortality throughout the world. Although treatment of DM with insulin injections and diet has increased the life span of diabetics, controversy continues about whether such treatment influenced the debilitating vascular complications that characterize DM. It is generally agreed that dysfunction of the islets of Langerhans in the pancreas is the primary abnormality in DM, so that transplantation of the pancreas represents a potentially curative form of therapy that warrants serious investigation. Such investigation must involve research conducted in animal models of DM because of the high risks and many years of observation that studies in human patients must entail. One such animal model is the alloxan diabetic rat in which we and others have documented the development and progression of severe nephropathy, neuropathy, retinopathy and microangiopathy that are strikingly similar to the lesions found in human DM. The crucial unanswered question about the clinical use of pancreas transplantation is: can pancreas transplants reverse or, at least, stabilize the established pathologic lesions of DM? The answer to this question has important implications regarding the treatment of DM as well as regarding its pathogenesis. To answer this all-important question, we have done extensive preparatory work during the past two years in which we have treated a large colony of highly inbred rats with severe alloxan DM by whole pancreas transplantation at 6, 12, 15, 18 and 21 months after onset of DM. These rats have had detailed metabolic studies, and they are being sacrificed at monthly intervals for up to 2 years after induction of DM. The critical work that remains to be done, and the crux of this grant proposal, is to determine, by quantitative morphometric methods established in our laboratory, if the pancreas transplants have reversed or stabilized the established diabetic lesions in the kidneys, nerves, eyes and microvasculature. The results of these studies are very likely to be applicable to patients with DM, particularly to those with the insulin-dependent form of the disease.